IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60080-1.html
   My bibliography  Save this article

Endocannabinoids disinhibit the ventral tegmental nucleus of Gudden to dorsal premammillary nucleus pathway to enhance escape behavior following learned threat experience

Author

Listed:
  • Ruikai Chai

    (Fudan University)

  • Nawen Wang

    (Fudan University)

  • Jinlu Nie

    (Fudan University)

  • Zongyi Xu

    (Fudan University)

  • Shuqian Zhang

    (Fudan University)

  • Suixin Deng

    (Fudan University)

  • Rongxin Wang

    (Fudan University)

  • Mu Li

    (Fudan University)

  • Xinyi Gao

    (Fudan University)

  • Ruijie Geng

    (Fudan University)

  • Haibin Li

    (Fudan University)

  • Lei Li

    (Fudan University)

  • Hebi Wu

    (Fudan University)

  • Zhiming Li

    (Fudan University)

  • Tian-Lin Cheng

    (Fudan University)

  • Xiao-Hong Xu

    (Fudan University)

  • Yousheng Shu

    (Fudan University)

  • Huilin Hong

    (Fudan University)

  • Xiao Huang

    (Fudan University)

  • Weisheng Wang

    (Fudan University)

Abstract

Innate escape behaviors, while not requiring prior learning, are shaped by an animal’s learned experiences, such as previous exposure. Here, we found that learned threat experience in mice enhances flight behaviors, which is linked to increased activation of cholecystokinin-expressing neurons in the dorsal premammillary nucleus (PMdCCK neurons), a population that controls circa-strike escape responses. This heightened activity coincides with reduced inhibition from parvalbumin-expressing GABAergic neurons in the ventral tegmental nucleus of Gudden (VTgPV), which typically suppress PMdCCK activity and escape behaviors. Furthermore, threat memory prompts a prefrontal projection to stimulate the release of endocannabinoids, inhibiting the axon terminals of VTgPV neurons. The necessity of this endocannabinoid-mediated disinhibition for the observed enhancement in flight behaviors is confirmed through genetic deletion or pharmacological blockade of endocannabinoid receptors on VTgPV neurons. Thus, our study uncovers a neural mechanism by which experience amplifies innate escape behaviors, highlighting the crucial role of endocannabinoids.

Suggested Citation

  • Ruikai Chai & Nawen Wang & Jinlu Nie & Zongyi Xu & Shuqian Zhang & Suixin Deng & Rongxin Wang & Mu Li & Xinyi Gao & Ruijie Geng & Haibin Li & Lei Li & Hebi Wu & Zhiming Li & Tian-Lin Cheng & Xiao-Hong, 2025. "Endocannabinoids disinhibit the ventral tegmental nucleus of Gudden to dorsal premammillary nucleus pathway to enhance escape behavior following learned threat experience," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60080-1
    DOI: 10.1038/s41467-025-60080-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60080-1
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-60080-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Xiao-lin Chou & Xiyue Wang & Zheng-gang Zhang & Li Shen & Brian Zingg & Junxiang Huang & Wen Zhong & Lukas Mesik & Li I. Zhang & Huizhong Whit Tao, 2018. "Inhibitory gain modulation of defense behaviors by zona incerta," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    2. Nigel Whittle & Jonathan Fadok & Kathryn P. MacPherson & Robin Nguyen & Paolo Botta & Steffen B. E. Wolff & Christian Müller & Cyril Herry & Philip Tovote & Andrew Holmes & Nicolas Singewald & Andreas, 2021. "Central amygdala micro-circuits mediate fear extinction," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Philip Tovote & Maria Soledad Esposito & Paolo Botta & Fabrice Chaudun & Jonathan P. Fadok & Milica Markovic & Steffen B. E. Wolff & Charu Ramakrishnan & Lief Fenno & Karl Deisseroth & Cyril Herry & S, 2016. "Midbrain circuits for defensive behaviour," Nature, Nature, vol. 534(7606), pages 206-212, June.
    4. Shicheng Zhang & Ryan H. Gumpper & Xi-Ping Huang & Yongfeng Liu & Brian E. Krumm & Can Cao & Jonathan F. Fay & Bryan L. Roth, 2022. "Molecular basis for selective activation of DREADD-based chemogenetics," Nature, Nature, vol. 612(7939), pages 354-362, December.
    5. Jing-Jing Yan & Xiao-Jing Ding & Ting He & Ai-Xiao Chen & Wen Zhang & Zi-Xian Yu & Xin-Yu Cheng & Chuan-Yao Wei & Qiao-Dan Hu & Xiao-Yao Liu & Yan-Li Zhang & Mengge He & Zhi-Yong Xie & Xi Zha & Chun X, 2022. "A circuit from the ventral subiculum to anterior hypothalamic nucleus GABAergic neurons essential for anxiety-like behavioral avoidance," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Ami Ritter & Shlomi Habusha & Lior Givon & Shahaf Edut & Oded Klavir, 2024. "Prefrontal control of superior colliculus modulates innate escape behavior following adversity," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Dominic A. Evans & A. Vanessa Stempel & Ruben Vale & Sabine Ruehle & Yaara Lefler & Tiago Branco, 2018. "A synaptic threshold mechanism for computing escape decisions," Nature, Nature, vol. 558(7711), pages 590-594, June.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Fernando M. C. V. Reis & Sandra Maesta-Pereira & Matthias Ollivier & Peter J. Schuette & Ekayana Sethi & Blake A. Miranda & Emily Iniguez & Meghmik Chakerian & Eric Vaughn & Megha Sehgal & Darren C. T, 2024. "Control of feeding by a bottom-up midbrain-subthalamic pathway," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Suma Chinta & Scott R. Pluta, 2023. "Neural mechanisms for the localization of unexpected external motion," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Clément Solié & Alessandro Contestabile & Pedro Espinosa & Stefano Musardo & Sebastiano Bariselli & Chieko Huber & Alan Carleton & Camilla Bellone, 2022. "Superior Colliculus to VTA pathway controls orienting response and influences social interaction in mice," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Coralie Hérent & Séverine Diem & Giovanni Usseglio & Gilles Fortin & Julien Bouvier, 2023. "Upregulation of breathing rate during running exercise by central locomotor circuits in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Jacob D Davidson & Ahmed El Hady, 2019. "Foraging as an evidence accumulation process," PLOS Computational Biology, Public Library of Science, vol. 15(7), pages 1-25, July.
    6. Jun Wang & Qian Yang & Xue Liu & Jie Li & Ya-Lan Wen & Yuzheng Hu & Tian-Le Xu & Shumin Duan & Han Xu, 2024. "The basal forebrain to lateral habenula circuitry mediates social behavioral maladaptation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Ami Ritter & Shlomi Habusha & Lior Givon & Shahaf Edut & Oded Klavir, 2024. "Prefrontal control of superior colliculus modulates innate escape behavior following adversity," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. Galván, Antonio & Haas, Jannik & Moreno-Leiva, Simón & Osorio-Aravena, Juan Carlos & Nowak, Wolfgang & Palma-Benke, Rodrigo & Breyer, Christian, 2022. "Exporting sunshine: Planning South America’s electricity transition with green hydrogen," Applied Energy, Elsevier, vol. 325(C).
    9. Hong Yu & Xinkuan Xiang & Zongming Chen & Xu Wang & Jiaqi Dai & Xinxin Wang & Pengcheng Huang & Zheng-dong Zhao & Wei L. Shen & Haohong Li, 2021. "Periaqueductal gray neurons encode the sequential motor program in hunting behavior of mice," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    10. Yue Zhao & Jin-Tao Wu & Jia-Bin Feng & Xin-Yu Cai & Xin-Tai Wang & Luxi Wang & Wei Xie & Yan Gu & Jun Liu & Wei Chen & Lin Zhou & Ying Shen, 2025. "Dual and plasticity-dependent regulation of cerebello-zona incerta circuits on anxiety-like behaviors," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    11. Anna J. Bowen & Y. Waterlily Huang & Jane Y. Chen & Jordan L. Pauli & Carlos A. Campos & Richard D. Palmiter, 2023. "Topographic representation of current and future threats in the mouse nociceptive amygdala," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    12. Chloe Hegoburu & Yan Tang & Ruifang Niu & Supriya Ghosh & Rodrigo Triana Del Rio & Isabel de Araujo Salgado & Marios Abatis & David Alexandre Mota Caseiro & Erwin H. Burg & Christophe Grundschober & R, 2024. "Social buffering in rats reduces fear by oxytocin triggering sustained changes in central amygdala neuronal activity," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    13. Wei Shang & Shuangyi Xie & Wenbo Feng & Zhuangzhuang Li & Jingyan Jia & Xiaoxiao Cao & Yanting Shen & Jing Li & Haibo Shi & Yiran Gu & Shi-Jun Weng & Longnian Lin & Yi-Hsuan Pan & Xiao-Bing Yuan, 2024. "A non-image-forming visual circuit mediates the innate fear of heights in male mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    14. Liu Liu & Kimberley El & Diptadip Dattaroy & Luiz F. Barella & Yinghong Cui & Sarah M. Gray & Carla Guedikian & Min Chen & Lee S. Weinstein & Emily Knuth & Erli Jin & Matthew J. Merrins & Jeffrey Roma, 2024. "Intra-islet α-cell Gs signaling promotes glucagon release," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    15. Sandeep Sharma & Cecilia A. Badenhorst & Donovan M. Ashby & Stephanie A. Vito & Michelle A. Tran & Zahra Ghavasieh & Gurleen K. Grewal & Cole R. Belway & Alexander McGirr & Patrick J. Whelan, 2024. "Inhibitory medial zona incerta pathway drives exploratory behavior by inhibiting glutamatergic cuneiform neurons," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    16. Camila Demaestri & Margaux Pisciotta & Naira Altunkeser & Georgia Berry & Hannah Hyland & Jocelyn Breton & Anna Darling & Brenna Williams & Kevin G. Bath, 2024. "Central amygdala CRF+ neurons promote heightened threat reactivity following early life adversity in mice," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    17. Takashi Nagashima & Suguru Tohyama & Kaori Mikami & Masashi Nagase & Mieko Morishima & Atsushi Kasai & Hitoshi Hashimoto & Ayako M. Watabe, 2022. "Parabrachial-to-parasubthalamic nucleus pathway mediates fear-induced suppression of feeding in male mice," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    18. Jasmin A. Strickland & Michael A. McDannald, 2022. "Brainstem networks construct threat probability and prediction error from neuronal building blocks," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    19. Wessel A. C. Burger & Vi Pham & Ziva Vuckovic & Alexander S. Powers & Jesse I. Mobbs & Yianni Laloudakis & Alisa Glukhova & Denise Wootten & Andrew B. Tobin & Patrick M. Sexton & Steven M. Paul & Chri, 2023. "Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    20. Alyse Thomas & Weiguo Yang & Catherine Wang & Sri Laasya Tipparaju & Guang Chen & Brennan Sullivan & Kylie Swiekatowski & Mahima Tatam & Charles Gerfen & Nuo Li, 2023. "Superior colliculus bidirectionally modulates choice activity in frontal cortex," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60080-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.